Collectins and ficolins, present in plasma and on mucosal surfaces, are humoral molecules of the innate immune systems, which recognize pathogen-associated molecular patterns. The human collectins, mannan-binding lectin (MBL) and surfactant protein A and D (SP-A and SP-D), are oligomeric proteins composed of carbohydrate-recognition domains (CRDs) attached to collagenous regions and are thus structurally similar to the ficolins, L-ficolin, M-ficolin, and H-ficolin. However, they make use of different CRD structures: C-type lectin domains for the collectins and fibrinogen-like domains for the ficolins. Upon recognition of the infectious agent, MBL and the ficolins initiate the lectin pathway of complement activation through attached serine proteases (MASPs), whereas SP-A and SP-D rely on other effector mechanisms: direct opsonization, neutralization, and agglutination. This limits the infection and concurrently orchestrates the subsequent adaptive immune response. Deficiencies of the proteins may predispose to infections or other complications, e.g., reperfusion injuries or autoimmune diseases.
Binding of collectins and ficolins to microbes through the lectin domains leads to activation of multiple immunological processes such as complement activation and phagocytosis. Collectins have also been shown to modulate leukocyte chemotaxis, proliferation and differentiation. Some of these processes are not necessarily dependent on the lectin activity of these molecules.
The complement system is an important arm of innate immunity and is found predominantly in the blood circulation as a serine protease cascade that can be triggered by different mechanisms. Complement activation on the surface of a microorganism kills microbes through lysis and then opsonizes microbial skeletons for effective phagocytosis through deposition of complement fragments. The complement cascade can be activated through three distinct pathways, that is,the classical, alternative and lectin pathways. For example, the activation of the classical pathway requires presensitization of microbes with antibodies that are recognized by C1q. C1q is associated with the C1r and C1s serine protease proenzymes as a complex called C1 and, upon binding of C1q to antigen-bound IgG and IgM, C1r and C1s are activated which subsequently recruit and activate C4 and C2. Activated C4 and C2 form C3 convertase that recruits and activates C3 leading to the formation of membrane attack complexes and microbial lysis. The activated C3 and C4, that is, C3b and C4b, are covalently deposited on the microbial surface which are recognized by phagocytic receptors on multiple phagocytes.
Collectins and ficolins have been reported to promote phagocytosis of various microorganisms, either directly after binding to microbes, or indirectly through upregulation of phagocytosis mediated by other phagocytic receptors. MBL and L-ficolin can indirectly opsonize microbes with complement opsonins C3b and C4b for enhanced phagocytosis without interaction with a MBL or ficolin receptor on phagocytes. Collectins and ficolins can also function as opsonins, which require interaction of these proteins with phagocyte receptors. Such receptors have not been identified for ficolins. However, a number of putative receptors/binding proteins, for the collectins, have been identified, including calreticulin, C1qRp, SPR-210, gp340, CD91, CR1 and CD14. Among these receptors, calreticulin and C1qRp have been shown to bind to multiple collectins. SPR-210 and gp340 only exhibited affinity for SP-A and SP-D. Both CD91 and CR1 bind to MBL. In fact, MBL mediates phagocytosis of apoptotic cells by binding to calreticulin on apoptotic cells and CD91 on phagocytes. C1qRp is a receptor that mediates immobilized collectin-induced upregulation of phagocytosis through complement and Fc receptors. However, C1qRp (CD93), defined initially as a receptor on the basis of its involvement in the enhancement of phagocytosis by monocytes, appears now to be involved in adhesion events, rather than C1q-mediated phagocytosis. SP-A has also been reported to promote phagocytosis of M. tuberculosis indirectly through upregulation of the activity of the mannose receptor but, SP-A receptor involved, remains to be characterized. Soluble CD14 has recently been shown to bind to SP-A, SP-D and MBL. CD14 is a recognition component of the LPS receptor complex that elicits inflammatory reactions upon binding to LPS. The collectins may therefore regulate the expression of cytokines involved in inflammation.
1. van de Wetering J K, et al. (2004). Collectins. European Journal of Biochemistry, 271(7), 1229-1249.
2. Lynch N J, et al. (2004). L-ficolin specifically binds to lipoteichoic acid, a cell wall constituent of Gram-positive bacteria, and activates the lectin pathway of complement. The Journal of Immunology, 172(2), 1198-1202.